Wednesday, May 20, 2015

Last night, I headed down to the beautiful Bell House, in the Gowanus section of Brooklyn, for this month's Secret Science Club lecture, featuring computational geneticist Dr Joe Pickrell of the New York Genome Center and Genomes Unzipped. Dr Pickrell's subject for his lecture was the use of genome sequencing for reconstructing human history and for understanding health variants.

As of 2015, approximately 1% of the population of the United States has undergone genome sequencing. It is technologically feasible to sequence the genomes of hundreds of millions of persons.

Dr Pickrell gave us a quick overview of human genetics- a typical human's DNA is contained in 46 chromosomes, 23 of which are inherited from each parent. There are four distinct bases in a DNA molecule: Guanine, Adenine, Cytosine, and Thymine. The human genome is composed of 3.3 billion bases, and different people vary at millions of these sites. Most of these genetic differences do nothing, therefore most genome variants are not informative about an individual's ancestry, but some differences are indicative. In one case, African ancestry can be inferred when an individual has an A-allele while individuals of East Asian descent tend to have a corresponding G-allele. It is useful to focus on a single "piece" of DNA- each piece has a different geneology. One question which can be asked is, "In each part of my genome, who are my closest ancestors?" The DNA record is valuable because it goes back further than the historical record, and can reveal much about what happened during human prehistory.

One promising area for the use of genome sequencing is elucidating the spread of agriculture from the Near East to the rest of Eurasia- agriculture reached as far as Scandinavia by approximately 4,000 BCE. Archaeological evidence, in the form of pottery styles, was used to make inferences about prehistoric cultural groups, with the dramatic spread of the Corded Ware Culture from 2,900-2,400 BCE being seen as evidence of a possible conquest. How does one interpret the spread of technology and languages? Was agriculture spread by conquerors who had the advantage of farming know-how, or was it simply a great idea that spread from group to neighboring group? Archaeologist M. Dores Cruz observed, "Pots are pots, not people." With genome sequencing, DNA can be connected to pottery types.

In order to determine the affinities of Neolithic populations, DNA samples were taken from different timepoints from a variety of archaeological sites. An ancestry analysis of modern Europeans indicates that they are the result of the mixture of several populations over the last ten thousand years- hunter-gatherers, Neolithic farmers, and Yamna invaders (known for their Kurgan... insert Clancy Brown reference... burials). These invaders came from the Eurasian steppes during the early Iron Age. Further back in prehistory, genetic analysis indicated that the genomes of Europeans has an admixture of Neanderthal DNA. The focus on Europe is because there has been a lot of collaboration between archaeologists and geneticists.

The Neanderthal genome has now been sequenced, and it was discovered that non-African peoples have approximately 2% Neanderthal DNA, and it is possible that certain African populatiojns have .02% Neanderthal DNA. Dr Pickrell showed a hilariously "spicy" promo from a Sex in the Stone Age documentary to highlight the Neanderthal admixture. At any rate, everyone's ancestry involves population movements and mixtures.

Dr Pickrell then shifted to the topic of understanding variations in health- for instance, genetic predispositions to conditions such as Alzheimer's disease. There are genetic variants which are associated with disease. Among populations of African descent the Duffy null allele (which is absent from European and Asian populations) plays a role in resistance to malaria.

Genetic variants influence all traits- hundreds of genetic variations influence height, thousands of variants influence a predisposition to schizophrenia. From a therapeutic standpoint, the task is to find the important genetic variants and figure out how they work.

One important recent study was conducted by Kaiser Permanente, which sequenced the DNA of 100,000 of its members. In the case of Alzheimer's, allele frequency was graphed with age to predict the onset of death or incapacitation. Knowledge of the effect of different alleles could potentially lead to the ability to "edit" DNA in order to deliver a genetic variant more conducive to good health. The genome isn't the only factor, of course, epigenetic factors such as environmental conditions, smoking, and exercise also play a role.

After the lecture, there was an extended Q&A session. One audience member asked about the oldest usable DNA that has been found, which belonged to a 700,000 year old horse (alas, no pet dinosaurs... yet). Another audience member asked about the genetics of autism. Dr Pickrell indicated that the most severe forms of autism are due to de novo mutations, but that other forms of autism result from a combination of different alleles. My friend Neil, who has his ear to the ground regarding all sorts of events, asked about genetic differences between Ashkenazi and Sephardic Jews, given the relatively small population size among their 2,000 year old ancestors (I'd chalk most population differences to epigenetic factors, such as the role of couscous vs latkes in the diet). Another audience member asked about the possible use of retroviruses to insert "corrections" into the DNA of individuals with genetic diseases. Riffing on this, some bastard in the audience asked about the timeline of the action of endogenous retroviruses- did they tend to accumulate early on in primate evolution? Did any significant retrovirus accretion take place after the big "out of Africa" movement of Homo sapiens? Dr Pickrell indicated that most of the endogenous retrovirus accretion took place long before H. sapiens made its debut, with a burst of activity occurring early on in primate evolution. Yet another audience member asked about the possibility of "genetic memory". Dr Pickrell noted that it is hotly debated, and that there is evidence that the Dutch famine of 1944 did play an epigenetic role that may have altered the genomes of its survivors' children.

Once again, the Secret Science Club served up a fantastic lecture, followed by a particularly spirited Q&A session. Dr Pickrell and his wife hung out at the bar for a good long time after the lecture, continuing the discussion. Kudos to the good doctor, the staff of the beautiful Bell House, and Margaret and Dorian!

Here's an hourlong lecture by Dr Pickrell for your education and enjoyment:

Crack open a beer or six and attempt to capture that Secret Science vibe...

About Me

The Big Bad Bald Bastard is a character played by Monsieur _______ of the City of Y______. The role of the Bastard is a handy one to play on subways, walking the streets, and in dive-bars, when being a nerdy, bookish sort is not to one's advantage.